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Genetically Diverse Mouse Embryonic Stem Cells: A Platform for Cellular Systems Genetics

Award Number: R24OD030037
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Genetically Diverse Mouse Embryonic Stem Cells: A Platform for Cellular Systems Genetics - PROJECT SUMMARY The objective of this application is to generate a thoroughly-validated panel of genetically diverse mouse embryonic stem cells (mESC) that will enable widespread adoption of cellular systems genetics. Phenotypic variation, manifesting as heterogeneity in cell state, represents a significant challenge for realizing the full promise of individualized, cell-based therapies, regenerative medicine. But phenotypic variation in genetically diverse stem cells also presents an opportunity for the advancement of large scale, cellular screens of gene by environment interactions (e.g. pharmacogenomics, toxicogenomics). A variety of approaches are beginning to identify the networks that drive cell state transitions, but these efforts have largely focused on bulk assays, which do not provide sufficient resolution of cell state heterogeneity, and mask the contribution of underlying genetic variation on rare cell types. Moreover, genetic studies using human pluripotent stem cells are largely limited to testing common variants due to low allele frequencies and imbalanced population structure requiring prohibitively large samples and impeding identification of core regulatory networks with high power and resolution. Therefore, we currently lack a thorough understanding of the genes and mechanisms that underlie phenotypic variation in pluripotent stem cells. The Diversity Outbred (DO) mouse population at The Jackson Laboratory is genetically defined, diverse, and presents a singular, cost-effective opportunity to systematically investigate heterogeneity in mammalian pluripotency. Our pilot studies using DO mESCs establish the feasibility of identifying regulatory loci at high power and resolution, as well as networks conserved in mice and humans that regulate cell state transitions. In Aim 1, we will create a reference mapping panel of 300 DO mESC lines that will serve as a gold standard resource for cellular systems genetics. This panel will be fully credentialed and banked for broad availability through The Jackson Laboratory / Mutant Mouse Resource and Research Centers (MMRRC). In Aim 2, we will determine at the single cell level the transcriptional networks that regulate cell state transitions in vitro through the early stages of differentiation to mesoderm in a representative subset of 144 lines. In Aim 3, we will map quantitative trait loci (QTL) that underlie variation in cell state-specific gene expression and in the distribution of cell states in a population. In addition, we will build and test models based on polygenic scores that can predict differentiation propensity from genotype. Finally, a web-based searchable database of expression phenotypes and interactive tools for visualization of cell composition and eQTL will be made publicly available to support community queries and hypothesis generation. In sum, we will produce a resource of cell lines and gene expression data for the research community that will spur new discoveries in regenerative medicine, pharmacogenomics, and toxicogenomics.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$14 )
2025	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Research Infrastructure Programs	000	4	7/25/2025	NON-COMPETING CONTINUATION	-$14
														Subtotal = -$14

Issue Date FY: 2024 ( Subtotal = $787,474 )
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Research Infrastructure Programs	001	4	5/14/2024	NON-COMPETING CONTINUATION	$131,554
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Research Infrastructure Programs	000	4	2/9/2024	NON-COMPETING CONTINUATION	$655,920
														Subtotal = $787,474

Issue Date FY: 2023 ( Subtotal = $814,159 )
2023	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Research Infrastructure Programs	000	3	2/15/2023	NON-COMPETING CONTINUATION	$814,159
														Subtotal = $814,159

Issue Date FY: 2022 ( Subtotal = $816,289 )
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Research Infrastructure Programs	001	2	5/24/2022	NON-COMPETING CONTINUATION	$81,629
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Research Infrastructure Programs	000	2	2/14/2022	NON-COMPETING CONTINUATION	$734,660
														Subtotal = $816,289

Issue Date FY: 2021 ( Subtotal = $823,759 )
2021	2021	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Research Infrastructure Programs	000	1	2/26/2021	NEW	$823,759
														Subtotal = $823,759

Grand Total All Awards = $3,241,667

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Genetically Diverse Mouse Embryonic Stem Cells: A Platform for Cellular Systems Genetics

Award Number: R24OD030037

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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